Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment

ABSTRACT

Compounds of formula (1) ##STR1## are described wherein Y represents a halogen atom or a group --OR 1 , where R 1  is an optionally substituted alkyl group; R 2  represents an optionally substituted cycloalkyl or cycloalkenyl group; R 3  is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen or sulphur atoms or a group --N(R 4 )-- where R 4  is a hydrogen atom or an alkyl group; X is --O--, --S--, or --N(R 5 )--, where R 5  is a hydrogen or an alkyl group; with the proviso that when X is --O-- then R 3  is not a 3-cyanamino-6-pyridazinyl or a 3-chloro-6-pyridazinyl group; and the salts, solvates, hydrates and N-oxides thereof. 
     The compounds are selective and potent inhibitors of phosphodiesterase IV and are useful for the prophylaxis and treatment of inflammatory diseases and the alleviation of conditions associated with central nervous malfunction.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.08/141,873, filed Oct. 22, 1993 now abandoned.

FIELD OF THE INVENTION

This invention relates to a novel series of tri-substituted phenylderivatives, to processes for their preparation, to pharmaceuticalcompositions containing them, and to their use in medicine.

BACKGROUND TO THE INVENTION

Many hormones and neurotransmitters modulate tissue function byelevating intra-cellular levels of adenosine 3',5'-cyclic monophosphate(cAMP). The cellular levels of cAMP are regulated by mechanisms whichcontrol synthesis and breakdown. The synthesis of cAMP is controlled byadenylyl cyclase which may be directly activated by agents such asforskolin or indirectly activated by the binding of specific agonists tocell surface receptors which are coupled to adenylyl cyclase. Thebreakdown of cAMP is controlled by a family of phosphodiesterase (PDE)isoenzymes, which also control the breakdown of guanosine 3',5'-cyclicmonophosphate (cGMP). To date, seven members of the family have beendescribed (PDE I-VII) the distribution of which varies from tissue totissue. This suggests that specific inhibitors of PDE isoenzymes couldachieve differential elevation of cAMP in different tissues, [forreviews of PDE distribution, structure, function and regulation, seeBeavo & Reifsnyder (1990) TIPS, 11:150-155 and Nicholson et al (1991)TIPS, 12: 19-27].

There is clear evidence that elevation of cAMP in inflammatoryleukocytes leads to inhibition of their activation. Furthermore,elevation of cAMP in airway smooth muscle has a spasmolytic effect. Inthese tissues, PDE IV plays a major role in the hydrolysis of cAMP. Itcan be expected, therefore, that selective inhibitors of PDE IV wouldhave therapeutic effects in inflammatory diseases such as asthma, byachieving both anti-inflammatory and bronchodilator effects.

The design of PDE IV inhibitors has met with limited success to date, inthat many of the potential PDE IV inhibitors which have been synthesisedhave lacked potency and/or have been capable of inhibiting more than onetype of PDE isoenzyme in a non-selective manner. Lack of a selectiveaction has been a particular problem given the widespread role of cAMPin vivo and what is needed are potent selective PDE IV inhibitors withan inhibitory action against PDE IV and little or no action againstother PDE isoenzymes.

A series of 3-cyanamino- and 3-chloro-(4-alkoxyphenyl)pyridazinecompounds are described in European Patent Specification No. 393500.Certain of these compounds are claimed to have broncholoytic andanti-inflammatory activities.

SUMMARY OF THE INVENTION

We have now found a novel series of tri-substituted phenyl derivatives,members of which are potent inhibitors of PDE IV at concentrations atwhich they have little or no inhibitory action on other PDE isoenzymes.These compounds inhibit the isolated PDE IV enzyme and also elevate cAMPin isolated leukocytes. Certain compounds prevent inflammation in thelungs induced by carrageenan, platelet-activating factor (PAF),interleukin-5 (IL-5) or antigen challenge. These compounds also suppressthe hyperresponsiveness of airway smooth muscle seen in inflamed lungs.Certain other compounds are also able to modulate central nervous system(CNS) function. The compounds of the invention are therefore of use inmedicine, especially in the prophylaxis and treatment of asthma, and forthe alleviation of conditions associated with dementia and other CNSmalfunctions.

Thus according to one aspect of the invention, we provide a compound offormula (1) ##STR2## wherein Y is a halogen atom or a group --OR¹, whereR¹ is an optionally substituted alkyl group;

R² is an optionally substituted cyoloalkyl or oycloalkenyl group;

R³ is a monocyclic or bicyclic aryl group optionally containing one ormore heteroatoms selected from oxygen or sulphur atoms or a group--N(R⁴)-- where R⁴ is a hydrogen atom or an alkyl group;

X is --O--, --S--, or --N(R⁵)--, where R⁵ is a hydrogen atom or an alkylgroup;, with the proviso that when X is --O-- then R³ is not a3-cyanamino-6-pyridazinyl or a 3-chloro-6-pyridazinyl group; and thesalts, solvates, hydrates and N-oxides thereof.

In the compounds of formula (1), when Y is a halogen atom it may be forexample a fluorine, chlorine, bromine or iodine atom.

When Y in the compounds of formula (1) is a group --OR¹, R¹ may be, forexample, an optionally substituted straight or branched alkyl group, forexample, an optionally substituted C₁₋₆ alkyl group, (e.g. a C₁₋₃ alkylgroup), such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl group. Optionalsubstitutents which may be present on R¹ groups include one or morehalogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms.

When R² in the compounds of formula (1) is an optionally substitutedcycloalkyl or cycloalkenyl group it may be for example a C₃₋₈-cycloalkyl group such as a cyclobutyl, cyclopentyl, or cyclohexyl groupor a C₃₋₈ -cycloalkenyl group such as a cyclobutenyl, cyclopentenyl orcyclohexenyl group, each cycloalkyl or cycloalkenyl group beingoptionally substituted by one, two or three substituents selected fromhalogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, C₁₋₆alkyl e.g. C₁₋₃ alkyl such as methyl or ethyl, hydroxyl or C₁₋₆ alkoxye.g. C₁₋₃ alkoxy such as methoxy or ethoxy groups.

Monocyclic or bicyolic aryl groups represented by the group R³ incompounds of formula (1) include for example C₆₋₁₂ optionallysubstituted aryl groups, for example optionally substituted phenyl or 1-or 2-naphthyl groups.

When the monocyclic or bicyclic aryl group contains one or moreheteroatoms it may be for example a C₃₋₉ optionally substitutedheteroaryl group containing for example one, two or three heteroatomsselected from oxygen or sulphur atoms or --N(R⁴)-- groups. Examples ofsuch groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl,thiazolyl, pyrazolyl, pyridinyl, e.g. 2-, 3- or 4-pyridinyl, pyrimidinyle.g. 5-pyrimidinyl, pyridazinyl e.g. 3-pyridazinyl or, 4-pyridazinyl,quinolinyl e.g. 4-quinolinyl, isoquinolinyl e.g. 4-isoquinolinyl,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl. Theheteroaryl group may be attached to the remainder of the molecule offormula (1) through any ring carbon or heteroatom as appropriate.

The aryl or heteroaryl groups represented by R³ in compounds of formula(1) may each optionally be substituted by one, two, three or moresubstituents [R⁶ ] selected from halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, or C₁₋₆ alkyl, e.g. methyl or ethyl, C₁₋₆alkoxy, e.g. methoxy or ethoxy, C₂₋₆ alkylenedioxy, e.g. ethylenedioxy,C₅₋₇ cycloalkoxy, e.g. cyclopentoxy, haloC₁₋₆ alkyl, e.g.trifiuoromethyl, C₁₋₆ alkylamino, e.g. methylamino or ethylamino, C₁₋₆alkylthyl, e.g. methylthio, amino (NH₂), aminoC₁₋₆ alkyl, e.g.aminomethyl or aminoethyl, C₁₋₆ dialkylamino, e.g. dimethylamino ordiethylamino, nitro, cyano, hydroxyl (OH), carboxyl (CO₂ H), --CO₂ R⁶[where R⁶ is a C₁₋₆ alkyl e.g. methyl or ethyl, C₆₋₁₂ arylC₁₋₃ alkyl,e.g. benzyl or phenethyl or C₆₋₁₂ aryl, e.g. phenyl group], C₁₋₆alkanoyl e.g. acetyl, sulphonyl (--SO₃ H), C₁₋₆ alkyl-sulphonyl, e.g.methylsulphonyl, aminosulphonyl (--SO₂ NH₂), C₁₋₆ alkyl-aminosulphonyl,e.g. methylaminosulphonyl or ethylamino-sulphonyl, C₁₋₆dialkylaminosulphonyl, e.g. dimethylaminosulphonyl ordiethyl..aminosulphonyl, carboxamido (--CONH₂), C₁₋₆alkylamino-carbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl,C₁₋₆ dialkylaminocarbonyl, e.g. dimethylaminocarbonyl ordiethylaminocarbonyl, sulphonylamino (--NHSO₂ H), C₁₋₆alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino,C₁₋₆ dialkylsulphonylamino, e.g. dimethylsulphonylamino ordiethylsulphonylamino C₁₋₆ alkanoylamino, e.g. acetylamino, or C₁₋₆alkanoylaminoC₁₋₆ alkyl, e.g. acetylaminomethyl groups.

It will be appreciated that where two or more R⁶ substituents arepresent, these need not necessarily be the same atoms and/or groups. TheR⁶ substituents may be present at any ring carbon atom away from thatattached to the rest of the molecule of formula (1). Thus, for example,in phenyl groups represented by R³ any substituent may be present at the2-, 3-, 4-, 5- or 6-positions relative to the ring carbon atom attachedto the remainder of the molecule.

When the groups --N(R⁴)-- or --N(R⁵)-- are present in the compounds offormula (1), R⁴ and R⁵ may each independently be a hydrogen atom or aC₁₋₆ alkyl group such as a methyl or ethyl group.

The presence of certain substituents in the compounds of formula (1) mayenable salts of the compounds to be formed. Suitable salts includepharmaceutically acceptable salts, for example acid addition saltsderived from inorganic or organic acids, and salts derived frominorganic and organic bases.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides,p-toluenesulphonates, phosphates, sulphates, acetates,trifluoroacetates, propionates, citrates, maleates, fumarates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases include alkali metal saltssuch as sodium or potassium salts, alkaline earth metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

One particular group of compounds of the invention has the formula (1)where R³ is an unsubstituted monocyclic or bicyclic aryl groupoptionally containing one or more heteroatoms selected from oxygen orsulphur atoms or a group --N(R⁴)--, and Y, R², R³, R⁴, R⁵ and X are asdefined for formula (1).

Another group of compounds according to the invention has the formula(1) where R³ is a monosubstituted monocyclic or bicyclic aryl groupoptionally containing a heteroatom selected from an oxygen or sulphuratom or a group --N(R⁴)--, and Y, R², R³, R⁴, R⁵ and X are as definedfor formula (1).

In the compounds of formula (1), the group Y is preferably an --OR¹group, especially where R¹ is an optionally substituted C₁₋₃ alkylgroup, particularly an ethyl group or, especially, a methyl group.Especially useful substitutents which may be present on R¹ groupsinclude one, two or three fluorine or chlorine atoms.

The group X in compounds of formula (1) is preferably --O--.

A particularly useful group of compounds of formula (1) has the formula(2): ##STR3## where R² is an optionally substituted cycloalkyl group; R³is as defined for formula (1) but is not a 3-cyanamino-6-pyridazinyl ora 3-chloro-6-pyridazinyl group; and the salts, solvates, hydrates andN-oxides thereof.

In the compounds of formulae (1) and (2) R² is preferably an optionallysubstituted cyclopentyl group. In particular, R² is a cyclopentyl group.

Particularly useful R³ groups in compounds of formulae (1) and (2)include substituted phenyl groups, especially 3- and/or 4-substitutedphenyl groups and naphthyl groups, especially 1-naphthyl. Particulargroups of these types include 3-nitrophenyl, 3-methoxyphenyl,4-methoxyphenyl, 3,4-dimethoxyphenyl and3-cyclopentyloxy-4-methoxyphenyl.

Other particularly useful R³ groups in compounds of formulae (1) and (2)include optionally substituted pyridinyl, particularly 3-pyridinyl and4-pyridinyl, optionally substituted pyrimidinyl, especially5-pyrimidinyl, and optionally substituted quinolinyl,5,6,7,8-tetrahydroquinolinyl, isoquinolinyl and5,6,7,8-tetrahydroisoquinolinyl, especially optionally substituted 3- or4-quinolinyl, 4-isoquinolinyl and 5,6,7,8-tetrahydroisoquinolin-4-yl.Optional substituents which may be present on these groups include, forexample, amino and methyl groups. Particularly useful substituted groupsof this type include 2-methylquinolin-4-yl and 1-aminoisoquinolin-4-yl.

A particularly useful group of compounds of the invention has theformula (1), especially the formula (2), wherein R³ is an optionallysubstituted pyrimidinyl group, especially an optionally substituted5-pyrimidinyl group.

A further particularly useful group of compounds of the invention hasthe formula (1), especially the formula (2) wherein R³ is anunsubstituted or monosubstituted pyridinyl group, in particular a3-pyridinyl, or, especially, a 4-pyridinyl group.

A still further particularly useful group of compounds of the inventionhas the formula (1), especially the formula (2) wherein R³ is anoptionally substituted isoquinolinyl group, in particular an optionallysubstituted 4-isoquinolinyl group.

Particularly useful compounds according to the invention are:

5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine;

4-(3-Cyclopentyloxy-4-methoxyphenyl)isoquinoline;

4-(3-Cyclopentyloxy-4-methoxyphenyl)pyridine;

2-Cyclopentyloxy-4-(3-cyclopentyloxy-4-methoxyphenyl)anisole;

4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylquinoline;

2-Cyclopentyloxy-4-(3-nitrophenyl)anisole;

4-(3-Cyclopentyloxy-4-methoxyphenyl)quinoline;

2-Cyclopentyloxy-4-(4-nitrophenyl)anisole;

4-(3-Cyclopentyloxy-4-methoxyphenyl)-2,3,5,6-tetrafluoropyridine;

5-Chloro-3-(3-cyclopentyloxy-4-methoxyphenyl)-2,4,6-trifluoropyridine;

5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine-2-carboxamide;

and the salts, solvates, hydrates and N-oxides thereof.

Compounds according to the invention are selective and potent inhibitorsof PDE IV. The ability of the compounds to act in this way may be simplydetermined by the tests described in the Examples hereinafter.

The compounds according to the invention are thus of particular use inthe prophylaxis and treatment of human diseases where an unwantedinflammatory response or muscular spasm is present and where theelevation of cAMP levels may be expected to prevent or alleviate theinflammation and relax the muscle. Compounds according to the inventionare also of particular use in the treatment of conditions associatedwith CNS malfunction.

Particular uses to which the compounds of the invention may be putinclude the prophylaxis and treatment of asthma, especially inflamedlung associated with asthma, or in the treatment of inflammatory airwaydisease, chronic bronchitis, eosinophillic granuloma, psoriasis andother benign and malignant proliferative skin diseases, endotoxic shock,septic shock, ulcerative colitis, Crohn's disease, reperfusion s injuryof the myocardium and brain, inflammatory arthritis, chronicglomerulonephritis, atopic dermatitis, urticaria, allergic rhinitis,adult respiratory distress syndrome, diabetes insipidus, allergicconjunctivitis and vernal conjunctivitis.

Compounds according to the invention may also elevate cAMP inlymphocytes and thereby suppress unwanted lymphocyte activation inimmune-based diseases such as rheumatoid arthritis, rheumatoidspondylitis, transplant rejection and graft versus host disease.

Compounds according to the invention may also be of particular use forthe alleviation of conditions associated with dementia and other CNSmalfunction for example in senile dementia (e.g. Alzheimer's disease),multiple infarct dementia and dementia caused by other agencies such asby brain tumours and by cerebral trauma.

For the prophylaxis or treatment of disease the compounds according tothe invention may be administered as pharmaceutical compositions, andaccording to a further aspect of the invention we provide apharmaceutical composition which comprises a compound of formula (1)together with one or more pharmaceutically acceptable carriers,excipients or diluents.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. starch orsodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (1) may be formulated for parenteraladministration by injection e.g. by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform e.g. in glass ampoule or multi dose containers, e.g. glass vials.The compositions for injection may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising, preserving and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater, before use.

In addition to the formulations described above, the compounds offormula (1) may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation for pressurised packs or anebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispense device may be accompanied byinstructions for administration.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular inflammatory condition will vary dependingon the compound chosen, and the condition of the patient to be treated.In general, however, daily dosages may range from around 100 ng/kg to100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral orbuccal administration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration, and around 0.5 mg to around 1000 mg for nasaladministration or administration by inhalation or insufflation.

The compounds according to the invention may be prepared by thefollowing processes. The symbols Y, R², R³ and X when used in theformulae below are to be understood to represent those groups describedabove in relation to formula (1) unless otherwise indicated.

Thus according to a further aspect of the invention, a compound offormula (1) may be prepared by coupling a boronic acid of formula (3)##STR4## and a compound R³ -L (where L is a leaving group, for example ahalogen atom such as a bromine or chlorine atom) in the presence of acomplex metal catalyst. Suitable catalysts include heavy metalcatalysts, for example palladium catalysts, such astetrakis(triphenylphosphine)palladium. The reaction may be performed inan inert organic solvent, for example an aromatic hydrocarbon such astoluene or benzene, or an ether such as dimethoxyethane or dioxane, inthe presence of a base, e.g. an alkali carbonate such as sodiumcarbonate, at an elevated temperature, e.g. the reflux temperature. Ingeneral, the metal catalyst and reaction conditions may be selected,depending on the nature of the boronic acid of formula (3) and/or thecompound R³ -L, from a range of known alternatives for reactions of thistype [see for example Miyaura, Net al, Synth. Commun. 1981, 11,513;Thompson, W. J. and Gaudino, J., J. Org. Chem., 1984, 49, 5237 andSharp, M. J. et al, Tetrahedron Lett., 1987, 28, 5093].

Intermediates R³ -L are either known compounds or may be prepared fromknown starting materials by methods analogous to those used for is thepreparation of the known compounds. Thus, for example, where it isdesired to obtain a compound R³ -L where L is a halogen atom such as abromine or chlorine atom and this compound is not readily available,such a compound may be prepared by diazotisation of the correspondingamine using for example a nitrite such as sodium nitrite in an aqueousacid at a low temperature followed by reaction with an appropriatecopper (I) halide in an aqueous acid.

Intermediate acids of formula (3) may be prepared by reaction of ahalide of formula (4) ##STR5## [where Hal is a halogen atom such as abromine or chlorine atom] by halogen--metal exchange with a base such asn-butyl or t-butyl lithium followed by a borate such astriisopropylborate optionally at a low temperature e.g. around -70° C.,in a solvent such as tetrahydrofuran.

Halides of formula (4) wherein X is --O--, --S-- or --N(R⁴)-- may beprepared by alkylation of a corresponding halide of formula (5) ##STR6##using a compound R² Hal where [Hal is as just defined] where necessaryin the presence of a base such as caesium or potassium carbonate or analkoxide such as potassium t-butoxide, in a dipolar aprotic solvent suchas an amide, e.g. a substituted amide such as dimethylformamide atambient temperature or above e.g. around 40° C. to 50° C.

Intermediates of formula (5) where X is --O-- may be prepared byoxidation of an aldehyde of formula (6) ##STR7## using an oxidisingagent such as 3-chloroperoxybenzoic acid in a halogenated hydrocarbonsuch as chloroform at a temperature from around 0° C. to roomtemperature.

Aldehydes of formula (6) and halides of formula (5) where X is --S-- or--N--(R⁴)-- are either known compounds or may be prepared from knownstarting materials by methods analogous to those used for thepreparation of the known compounds.

In another aspect of the invention a compound of formula (1) may beprepared by reaction of a halide of formula (4) with a borane R³ B(AIk)₂(where Alk is a C₁₋₄ alkyl group such as an ethyl group) or a boronicacid R³ B(OH)₂ using the reagents and conditions described above for thepreparation of compounds of formula (1) from acids of formula (2) [seefor example Ishikura, M et al, Synthesis, 1984, 936]. Intermediateboranes R³ B(AIk)₂ and boronic acids R³ B(OH)₂ for use in this processare either known compounds or may be prepared using methods analogous tothose used for the preparation of the known compounds.

In yet another aspect of the invention, a compound of formula (1) may beprepared by alkylation of a compound of formula (7) ##STR8## with ahalide R² Hal, as described above for the preparation of compounds offormula (4), or with an alcohol R² OH, and a phosphine, such astriphenylphosphine, and an activator, for example diethylazodicarboxylate, in the presence of an organic base such astriethylamine in a solvent such as tetrahydrofuran at an elevatedtemperature, e.g. the reflux temperature [see for example Mitsunobu, O.,Synthesis, 1981, 1].

Intermediates of formula (7) may be prepared by reaction of a boronicacid of formula (3) wherein R² is a hydrogen atom with a compound R³ -Las described above for the preparation of compounds of formula (1) fromacids of formula (3). In this reaction the group X-R² may need to be ina protected state. Conventional hydroxy, amino or thiol protectinggroups may be used in accordance with standard practice [see, forexample, Green, T. W. in "Protective Groups in Organic Synthesis" JohnWiley and Sons, 1981].

According to a still further aspect of the invention a compound offormula (1) may be prepared by reaction of an intermediate halide offormula (4) by halogen-metal exchange with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, followed by reaction with acompound R³ H, using for example the reagents and conditions describedabove for the preparation of Intermediates of formula (3) lo fromIntermediates of formula (4).

Compounds of formula (1) may also be prepared by interconversion ofother compounds of formula (1). Thus, for example, a compound of formula(1) where R³ contains an amino (--NH₂) substituent may be prepared froma corresponding compound where R³ contains a nitro group by reduction,using for example hydrogen in the presence of a metal such as platinumof palladium, optionally in the presence of an acid, such as aceticacid. Similar reduction conditions may also be used to convert acompound of formula (1) where R³ is a quinolinyl or isoquinolinyl groupto a corresponding compound where R³ is a 5,6,7,8-tetrahydroquinolinylor 5,6,7,8-tetrahydroisoquinolinyl group.

In another general example, a group represented by R³ in compounds offormula (1) may be substituted by any of the groups R⁵ by an appropriateaddition or displacement reaction using the corresponding unsubstitutedor substituted compound of formula (1) and a R⁵ containing nucleophileor electrophile. Thus for example to obtain a group R³ in compounds offormula (1) substituted by an amino (--NH₂) group, the correspondingunsubstituted compound may be reacted with an amide such as sodium amidein an inert solvent such as toluene, at an elevated temperature such asthe reflux temperature. In another example, to obtain a group R³ incompounds of formula (1) substituted by a cyano group, a correspondingcompound containing a displaceable R⁵ substituent, such as analkylsulphonyl group, may be reacted with a nitrile such as potassiumcyanide, at an elevated temperature. Similarly, compounds of formula (1)wherein R³ contains an amino or alkoxy, e.g. methoxy, substituent may beprepared by treatment of a corresponding compound wherein R³ contains adisplaceable R⁵ substituent with an alcoholic, e.g. methanolic, ammoniasolution followed by separation of the desired amino and alkoxycompounds.

In another example of an interconversion process, a compound of formula(1) wherein R³ contains a --CH₂ NH₂ substituent may be prepared byreduction of a corresponding compound wherein R³ contains a nitrilegroup, using for example a complex metal hydride such as lithiumaluminium hydride in a solvent such as an ether e.g. diethylether.

In a further example, a compound of formula (1) wherein R³ contains analkanoylamino or alkanolyaminoalkyl substituent may be prepared byacylation of a corresponding compound wherein R³ contains a --NH₂ oralkylamino group by reaction with an acyl halide in the presence of abase, such as a tertiary amine e.g. triethylamine in a solvent such asdichloromethane.

In yet another example of an interconversion process, a compound offormula (1) wherein R³ contains an alkylsulphonyl substituent may beprepared by oxidation of a corresponding compound wherein R³ contains analkylthio group using for example an oxidising agent such as a peroxyacid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as ahalogenated hydrocarbon, e.g. dichloromethane, at a low temperature,e.g. below 10° C.

In a still further example of an interconversion process according tothe invention, a compound of formula (1) wherein R³ contains acarboxamido (--CONH₂) substituent may be prepared by oxidation of acorresponding compound where R³ contains a cyano substituent, using anoxidising agent, for example hydrogen peroxide and a base such as sodiumhydroxide in a solvent such as an alcohol, e.g. ethanol. N-oxides ofcompounds of formula (1) may be prepared by oxidation of thecorresponding nitrogen base using an oxidising agent such as hydrogenperoxide in the presence of an acid such as acetic acid, at an elevatedtemperature, for example around 70° C. to 80° C., or a peroxyacid suchas 3-chloroperoxybenzoic acid in a solvent such as a halogenatedhydrocarbon, e.g. dichloromethane, at e.g. room temperature.

Salts of compounds of formula (1) may be prepared by reaction of acompound of formula (1) with an appropriate acid or base in a suitablesolvent using conventional procedures.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following examples illustrate the invention.

The following abbreviations are used:

    ______________________________________                                        DMF            dimethylformamide                                              THF            tetrahydrofuran                                                DME            dimethoxyethane                                                EtOAc          ethyl acetate                                                  Et.sub.2 O     diethylether                                                   RT             room temperature                                               t.l.c.         thin layer chromatography                                      ______________________________________                                    

INTERMEDIATE 1

5-Bromo-2-methoxyphenol

A solution of 5-bromo-2-methoxybenzaldehyde (100 g, 0.46 mol) inchloroform(250 ml) was cooled with an ice bath and 3-chloroperoxybenzoicacid (50-60%purity) (146 g, 0.51 mol) in chloroform (1000 ml) added. Thereaction mixture was allowed to warm slowly to room temperature andstirred for 72 h. The white solid was filtered off and the filtrateconcentrated in vacuo. The residue was dissolved in ether (200 ml) andwashed with 1M sodium sulphite solution (2×200 ml) then sodium hydrogencarbonate [half saturated] (3×200 ml). The ether layer was washed with10% aqueous sodium hydroxide (3×100 ml) and the combined basic extractwas acidified with concentrated hydrochloric acid and extracted with Et₂O (3×100 ml). The combined organic extract was dried (MgSO₄) andflorisil (10 g) filtered and the solvent removed under reduced pressureto give the title compound (90 g) as a pale brown solid.

INTERMEDIATE 2

4-Bromo-2-cyclopentyloxyanisole

Intermediate 1 (90 g) was dissolved in DMF (300 ml), and treated withCs₂ CO₃ (158 g, 490 mmol), and cyclopentylbromide (73 g, 52.5 ml, 490mmol). After stirring overnight, Cs₂ CO₃ (35 g, 107 mmol), andcyclopentylbromide (12 ml, 16.7 g, 112 mmol) were added and stirringcontinued for 2 h. A further portion of cyclopentylbromide (10 ml) andCs₂ CO₃ (14 g) were then added. After stirring for 1 h, the DMF wasevaporated in vacuo and the residue diluted with water (200 ml) andextracted with Et₂ O (3×100 ml). The combined organic extract was washedwith NaOH solution (5%, 2×100 ml), water (100 ml), then dried (MgSO₄)and the solvent evaporated in vacuo to give ared oil which was distilled(140° C., 0.3 mbar) to afford the title compound (101 g) as a colourlessoil Found: C, 53.11; H, 5.53. C₁₂ H₁₅ BrO₂ requires C, 53.15; H, 5.58%.

INTERMEDIATE 3

3-Cyclopentyloxy-4-methoxyphenylboronic acid

To a stirred solution of Intermediate 2 (8.0 g, 29.5 mmol) in dry THF(60 ml), at -70° C. under an argon atmosphere was added n-butyllithium(1.45M, 23.4 ml, 33.9 mmol) over 10 minutes. After stirring for afurther 30 minutes triisopropylborate (11.10 g, 13.6 ml, 59 mmol) wasadded at such a rate that the temperature did not exceed -60° C. Thereaction mixture was stirred at -60° C. for 10 mins then the coolingremoved and the reaction allowed to warm to room temperature (20 mins).After stirring for 2 h the reaction was quenched with 10% aqueous HClsolution and stirred for 0.5 h. The reaction mixture was extracted withEtOAc (3×40 ml) and the combined organic extract washed with brine (100ml), dried (MgSO₄) and the solvent removed in vacuo. The resulting whitesolid was heated to reflux in Et₂ O/hexane 1:3 then cooled to roomtemperature and the product filtered off. The filtrate was concentratedin vacuo and the residue flash column chromatographed [SiO₂ ;EtOAc/hexane, 1:9 (500 ml), then 1:1 (500 ml)] to afford a second crop.Total yield of the title compound was 5.23 g (m.p. 175°-177° C.). δ_(H)H(CDCl₃ ; 80 MHz) 1.6-2.1 (8H, br m, (CH₂)₄), 3.90 (3H, s, OMe), 4.89(1H, br m, OCHCH₂), 6.95 (1H, d, J8.0 Hz, ArHortho to OMe), 7.65-7.85(2H, m, 2xArH meta to OMe).

INTERMEDIATE 4

5-Bromoisoquinoline

To a cold (0° C.) solution of HBr-H₂ O (48%) (10 ml) in water (30 ml)was added 5-aminoisoquinoline (5 g; 35 mmol) followed by sodium nitrite(2.4 g; 35 mmol) in water (20 ml). The mixture was added to a warm(75°C.) solution of cuprous bromide (5 g; 35 mmol) in HBr-H₂ O(48%) (50 ml)and stirred overnight at 75° C. The reaction mixture was cooled,basified to pH11 with NaOH (5M) and steamed distilled to afford thetitle compound (1.4 g) as a colourless crystalline solid (mp 65° C.).

INTERMEDIATE 5

2-Methylthiopyrimidine

To a solution of potassium hydroxide (12 g) in methanol (30 ml) wasadded 2-mercaptopyrimidine (20 g). The mixture was stirred to achievetotal solubility before adding methyl iodide (25.36 g) while keeping thetemperature of the reaction below 30° C. with an ice-bath cooling. Thestirring was maintained for 2 h at RT before removing the solvent invacuo. The slurry was extracted with Et₂ O (500 ml), filtered andthesolution evaporated to afford a pale yellow oil. Filtration through asilica pad (Et₂ O/hexane, 1:1) gave, after evaporation, the titlecompound (21 g) as a colourless oil. δ_(H) (CDCl₃); 2.55 (3H,s, CH₃),6.94 (1 H, t, pyrimidine H₅), 8.46 (2H, d, J4.8 Hz, pyrimidine H₄, H₆).

INTERMEDIATE 6

5-Bromo-2-Methylthiopyrimidine

A reaction mixture containing Intermediate 5 (10 g), and bromine (12.7g) in carbon tetrachloride (200 ml) and in 1,2-dichloroethane (100 ml)was heated to gentle reflux for 3 days. The reaction mixture was pouredinto aqueous sodium sulphite (20%; 100 ml) and stirred until the orangecolour had largely disappeared. The pH was adjusted to 7 with 20% NaOHand the aqueous phase extracted with dichloromethane (3×100 ml). Thecombined organic phase was washed with brine (50 ml), dried (MgSO₄) andevaporated to give an oil. Flash chromatography [SiO₂ ; 10% Et₂O/hexane] gave the title compound as an off-white solid (mp 63°-65° C.).

EXAMPLE 1

a) 5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine hydrochloride

To a stirred solution of tetrakis(triphenylphosphine) palladium[O] (0.59g,0.51 mmol) in DME (150 ml) at room temperature under an argonatmosphere was added 5-bromopyrimidine (3.24 g, 20.4 mmol). Afterstirring for 20 minutes sodium carbonate (2M, 20.4 ml) was addedfollowed by Intermediate 3 (4.0 g, 17 mmol). The mixture was immediatelyrefluxed for 16 h then poured into half saturated NaCl solution (100ml). EtOAc (50 ml) was addedand the organic phase separated. The aqueousportion was extracted with EtOAc (100 ml) and the combined organicextract washed with brine, dried over MgSO₄ and the solvent evaporatedin vacuo to yield a clear oil. Flash column chromatography [SiO₂ ; Et₂O/hexane; 1:1 (1000 ml) then 7:3 (1000 ml)] furnished the title compoundfree base (4.49 g) as a white crystalline solid.

Treatment of the base with ethanolic HCl afforded the title compound asa pale yellow solid [m.p. 131°-147° C. (dec)]. Found: C, 62.33; H, 6.29;N, 9.03. C₁₆ H₁₈ N₂ O₂ HCl requires C,62.64; H, 6.24; N, 9.13%. δ_(H)(CDCl₃ ; 80 MHz) 1.6-2.1 (8H, br m, (CH₂)₄), 3.90 (3H, s, OMe), 4.87 (1H, br m, OCHCH₂),7.0-7.25 (3H, m, 1xortho and 2xmeta ArH to OMe), 9.23(2H, s, pyrimidine H₄, H₆), 9.28 (1 H, s, pyrimidine H₂), 10.60 (1 H, brs, NH).

The following compounds were prepared in a manner similar to thecompound of Example 1a).

b) 2-Chloro-5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine

From Intermediate 3 (1.04 g) and 5-bromo-2-chloropyridine (1.0 g). Flashcolumn chromatography [SiO₂ ; EtOAc/hexane, 1:9 then 2:8 then 2.5:7.5]yielded the title compound (1.02 g) as a white crystalline solid (mp88°-90° C.). Found: C, 63.10; H, 5.62; N, 9.15. C₁₆H₁₇ ClN₂ O₂ requiresC, 63.05; H, 5.62; N, 9.19%.

c) 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2,3,5,6-tetrafluoropyridine

From Intermediate 3 (1.01 g) and 4-bromo-2,3,5,6-tetrafluoropyridine(1.181g). Column chromatography [SiO₂ ; EtOAc] followed byrecrystallisationfrom hexane furnished the title compound (1.184 g)as anoff-white powder (mp 115°-116° C.). Found: C, 59.84; H, 4.55; N, 3.81.C₁₇ H₁₅ NO₂ F₄ requires C, 59.83; H, 4.43; N, 4.10%.

d)5-Chloro.-3-(3-Cyclopentyloxy-4-methoxyphenyl)-2,4,6-trifluoropyridine

From Intermediate 3 (1.085 g) and 3,5-dichloro-2,4,6-trifluoropyridine(1.13 g). Column chromatography [SiO₂ ; dichloromethane] furnished thetitle compound (1.125 g) as a white flaky powder (mp 100°-102° C.).Found: C, 57.14; H, 4.30; N, 3.83; Cl, 10.05.C₁₇ H₁₅ ClF₃ NO₂ requiresC, 57.07; H, 4.23; N, 3.92; N, 3.92; Cl, 9.91%.

e) 5-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylthio pyrimidine

From Intermediate 3 (1.04 g) and Intermediate 6 (1.06 g). Flash columnchromatography [SiO₂ ; Et₂ O/hexane, 1:2) furnished the title compound(550 mg) as a white crystalline solid (mp 84.5°-86.5° C.). Found C,64.47; H, 6.25; N, 8.74. C₁₇ H₂₀ N₂ O₂ S requires C, 64.55; H, 6.32; N,8.86%.

f) 1-(3-Cyclopentyloxy-4-methoxyphenyl)naphthalene

From Intermediate 3 (0.50 g) and 1-bromonaphtalene (0.526 g). Columnchromatography [SiO₂ ; EtOAc/hexane, gradient elution] gave thetitlecompound (0.485 g) as colourless crystals (mp 123°-125° C.). FoundC, 82.45; H, 6.96. C₂₂ H₂₂ O₂ requires C, 82.99; H, 6.96.

EXAMPLE 2

4-(3-Cyclopentyloxy-4-methoxyphenyl)isoquinoline

To DME (15 ml) filtered through alumina under nitrogen was addedtetrakis(triphenylphosphine)palladium[O] (51 mg, 0.044 mmol) and4-bromoisoquinoline (304 mg, 1.46 mmol). The reaction mixture wasstirred at room temperature for 20 min before adding aqueous sodiumcarbonate solution (2M, 1.46 ml) and Intermediate 3 (300 mg, 1.27 mmol).The mixturewas immediately heated to reflux. After 16 h the reactionmixture was poured into water (50 ml) and extracted with Et₂ O (3×40ml). The organic extract was washed with brine (50 ml), dried (MgSO₄),andthe solvent removed under reduced pressure. The crude oil wassubjected to flash chromatography (Et₂ O/hexane, 2:3 then 3:2) to affordthe titlecompound (396 mg) as a colourless oil, δ_(H) (CDCl₃ ; 80 MHz)1.6-2.1 (8H, br m, (CH₂)₄), 3.91 (3H, s, OMe), 4.77 (1H, br m, OCHCH₂),6.99 (3H, s, 1xortho and 2xmeta ArH to OMe), 7.5-7.7 (2H, m,isoquinoline H₆, H₇), 7.85-8.1 (2H, m, isoquinoline H₅, H₈), 8.43 (1H,s, isoquinoline H.sub. 3), 9.17 (1 H, s, isoquinoline H₁). m/z 319 (M⁺,30%), 252 (35), 251 (M⁺ -cyclopentyl, 100), 237 (12), 236 (63), 208(20), and 190 (11).

Treatment of the oil with ethereal HCl/ethanol afforded thehydrochloride salt as a pale yellow solid, [m.p. 171°-186° C.(dec) (fromacetone)]. Found: C, 70.83; H, 6.19; N. 3.82. C₂₁ H₂₁ NO₂.HCl requiresC, 70.88; H, 6.23; N, 3.94%.

EXAMPLE 3

a) 4-(3-Cyclopentyloxy-4-methoxyohenyl)pyridine hydrochloride

Tetrakis(triphenylphosphine)palladium [O] (5 mol %, 89 mg) was added toa solution of 4-bromopyridine hydrochloride (1.54 mol, 0.30 g) in DME(filtered through Grade 1 Alumina, 50 ml) and the mixture stirred underdry nitrogen for 15 minutes. Intermediate 3 (0.40 g, 1.69 mmol) wasadded as a solid followed by sodium carbonate solution (2M, 1.54 ml) andthen a further portion of sodium carbonate (0.1 g). The mixture wasimmediately heated to reflux. After 16 h, the mixture was cooled,diluted with Et₂ O (150 ml) and brine (100 ml), the organic layer wasseparated, dried (Na₂ SO₄) and concentrated in vacuo to give a brownoil. The oil was subjected to flash chromatography [Et₂ O/EtOAc (100:0to 50:50)] to yield the title compound free base (0.260 g) as a paleyellow solid.

Treatment of the base with ethanolic-ethereal HCl afforded the titlecompound as a white solid (m.p. 213°-222° C.) (dec). Found: C, 66.39; H.6.54; N, 4.49. C₁₇ H₁₉ NO₂.HCl requires C, 66.77; H, 6.59; N, 4.58%),δ_(H) (CDCl₃ ; 80 MHz) 1.6-2.1 (8H; br m, (CH₂)₄), 3.92 (3H, s, OMe),4.85 (1H, br m, OCHCH₂), 6.99 (1H, d, J 8.6 Hz, ArH ortho to OMe), 7.23(1H, d, J2.3 Hz, ArH ortho to cyclopentyloxy), 7.38 (1H, dd, J8.4, 2.3Hz, ArH para to cyclopentyloxy), 8.01 (2H, d, J7.0 Hz, pyridine H₃, H₅),8.75 (2H, d, J7.0 Hz, pyridine H₂, H₆); m/z 269 (M⁺ -HCl, 43%), 202(67), 201 (M⁺ -HCl-cyclopentyl), 187 (28), 186 (95), 183 (19), 158 (47),69 (12), 41 (57), and 36 (43).

The following compounds were prepared in a similar manner to thecompound of Example 38):

b) 2-(3-Cyclopentyloxy-4-methoxyphenyl)toluene

from Intermediate 3 (367 mg) and 2-bromotoluene (293 mg) to yield thetitlecompound (241 mg) as a colourless oil. Found: C, 80.67; H, 7.75.C₁₉ H₂₂ O₂ requires C, 80.82; H, 7.85%. m/z 282 (M⁺, 16%), 215 (15), 214(M⁺ -cyclopentyl, 100), 200 (11), 199 (32), 181 (15), 153 (12), 124(24), 109 (11) and 28 (27).

c) Methyl 3-(3-Cyclopentyloxy-4-methoxyphenyl)benzoate

from Intermediate 3 (430 mg) and methyl 3-bromobenzoate (356 mg) toyield the title compound (300 mg) as a colourless oil, ν_(max). (neat)2960, 1725, 1520, 1450, 1250, 805, 755 cm⁻¹. δ_(H) (CDCl₃ ; 80 MHz)1.5-2.1 (8H, br m, (CH₂)₄), 3.83 (3H, s, OMe), 3.89 (3H, s, OMe), 4.83(1H, br m, OCHCH₂), 6.86 (1H, d, J9 Hz,ArH ortho to OMe), 6.9-7.2 (2H,m, 2xArH meta to OMe), 7.44 (1H, d, J7.5 Hz, ArH meta, to CO₂ Me), 7.66(1 H, ca, dt, J7.5, 1.5 Hz, ArH para to CO₂ Me), 7.91 (1 H, ca.dt, J7.5,1.5 Hz, ArH para to aryl), 8.17 (1 H, ca.t, J1.5 Hz, ArH ortho to CO₂ Meand aryl); m/z 326 (M⁺,10%), 259 (16), 258 (M⁺ -cyclopentyl, 100), 244(9), 243 (54), 215 (17) and 41 (9).

d) 4-(4-Chlorophenyl)-2-(cyclopentyloxy)anisole

from Intermediate 3 (300 mg) and 4-bromochlorobenzene (292 mg) to yieldthetitle compound (213 mg) as a white solid [m.p. 88°-91° C. (fromhexane)]. Found: C, 71.74; H, 6.30. C₁₈ H₁₉ ClO₂ requires C, 71.40; H,6.32%.

e) 2-Cyclopentyloxy-4-(3-methoxyphenyl)anisole

from Intermediate 3 (1.01 g) and 3-bromoanisole (800 mg) to yield thetitlecompound (350 mg) as a white amorphous powder. Found: C, 76.51; H,7.46. C₁₉ H₂₂ O₃ requires C, 76.48; H, 7.43%) δ_(H) (CDCl₃ ; 80 MHz)1.5-2.1 (8H, br m (CH₂)4), 3.83 (3H, s, OMe), 3.85 (3H, s, OMe), 4.81(1H, br m, OCHCH₂), 6.7-7.4 (7H, m, ArH); m/z298(M⁺, 31%), 231 (15), 230(M⁺ -cyclopentyl 100), 215 (38), 200 (11), 187 (14) and 41 (14).

f) 2-Cyclopentyloxy-4-(3-cyclopentyloxy-4-methoxyohenyl) anisole

from Intermediate 3 and Intermediate 2 to yield the title compound aspale yellow flakes. Found: C, 75.11; H, 7.81. C₂₄ H₃₀ O₄ requires C,75.36; H, 7.91%.

g) 2-Cyclopentyloxy-4-(4-nitrophenyl)anisole

from Intermediate 3 (300 mg) and 1-bromo-4-nitrobenzene (300 mg) toyield the title compound (400 mg) as yellow needles, [m.p. 119°-120° C.(hexane)]. Found: C, 69.09; H, 6.02; N, 4.45. C₁₈ H₁₉ NO₄ requires C,69.00; H, 6.11; N, 4.47%) δ_(H) (CDCl₃ ; 80 mHz) 1.6-2.1 (8H, m,(CH₂)₄), 3.88 (3H, s, OMe), 4.83 (1H, br m, OCHCH₂), 6.85-7.20 (3H, ArHortho to OMe and 2xArH meta to OMe), 7.62 (2H, dm, J ca. 9 Hz, 2xArHmeta to NO₂); 8.22(2H, dm, Jca. 9 Hz, 2xArH ortho to NO₂); m/z 313 (M⁺,5%), 246 (15), 245 (M⁺ -cyclopentyl, 100), 230 (49), 149 (21), and 83(15).

h) 4-(3-Cyanophenyl)-2-(cyclopentyloxy)anisole

from Intermediate 3 (500 mg) and 3-bromobenzonitrile (440 mg) to yieldthe title compound (610 mg) as a white solid, [m.p. 70°-71° C.(hexane-toluene)]. Found: C, 77.72; H, 6.51; N, 4.80. C₁₉ H₁₉ NO₂requires C, 77.79; H, 6.53; N, 4.77%) δ_(H) (CDCl₃ ;80 mHz) 1.6-2.1 (8H,br m, (CH₂)₄), 3.84 (3H, s, OMe), 4.83 (1 H,br m, OCHCH₂), 6.85-7.15(3H, m ArH ortho and 2xArH meta to OMe), 7.2-7.8 (4H, m, 2xArH ortho and2xArH meta and ArH para to CN); m/z 293 (M⁺, 6%), 226 (16), 225 (M⁺-cyclopentyl), 211 (9), 210 (60 ), and 182 (17).

i) 2-(3-Cyclopentyloxy-4-methoxyohenyl)-5-nitropyridine

from Intermediate 3 (300 mg) and 2-bromo-5-nitropyridine (297 mg) toaffordthe title compound (405 mg) as a pale yellow solid, [m.p.110°-111° C. (diisopropyl ether)]. Found: C, 64.99; H, 5.74;N, 8.89. C₁₇H₁₈ N₂ O₄ requires C, 64.96; H, 5.74; N, 8.89 δ_(H) (CDCl₃ ; 80 mHz)1.5-2.1 (8H, br m, (CH₂)₄), 3.90 (3H, s, OMe), 4.90 (1 H, br m, OCHCH₂),6.92 (1 H, d, J8.5 Hz, ArH ortho to OMe), 7.58 (1 H, dd, J8.3, 2.0 Hz,ArH parato OMe), 7.70 (1 H, d, J1.4 Hz, ArH ortho to cyclopentyloxy),7.76 (1 H, d,J8.7 Hz, ArH meta to NO₂), 8.40 (1 H, dd, J8.8, 2.5 Hz,pyridine H₄), 9.37 (1 H, d, J2.5 Hz, pyridine H₂); m/z 314 (M⁺, 14%),247 (26), 246 (M⁺ -cyclopentyl,100), 231 (54), 203 (12), 173 (11), 41(11) 32 (15) and 28 (58).

j) 2-(3-Cyclopentyloxy-4-methoxyohenyl)thiophene

from Intermediate 3 (300 mg) and 2-bromothiophene (238 mg) to afford thetitle compound (345 mg) as white needles [(m.p. 67°-68° C.) (hexane)].Found: C, 69.96; H, 6.67. C₁₆ H₁₈ O₂ S requires C, 70.04; H, 6.61%;δ_(H) (CDCl₃ ; 80 mHz) 1.5-2.1 (8H, br m,(CH₂)₄), 3.83 (3H, s, OMe),4.80 (1 H, br m, OCHCH₂), 6.80 (1 H, d, J8.7 Hz, ArH ortho to OMe),6.9-7.2 (5H, m, 2xArH meta to OMe), and thiopone H₃, H₄, H₅); m/z 274(M⁺, 24%), 207 (13),206 (M⁺ -cyclopentyl, 100), 192 (10), 191 (85), 163(18), and 41 (12).

k) 5-(3-Cyclopentyloxy-4-methoxyphenyl)isoquinoline

from Intermediate 3 (228 mg) and Intermediate 4 (202 mg) to afford thetitle compound (299 mg) as a white crystalline solid [m.p. 115°-116° C.(acetone)]. Found: C, 78.71; H, 6.62; N, 4.30. C₂₁ H₂₁ NO₂ requires C,78.97; H, 6.63; N, 4.39% δ_(H) (CDCl₃ ; 80 mHz) 1.5-2.1 (8H, br m,(CH₂)₄), 3.90 (3H, s, OMe), 4.75 (1 H, br m, OCHCH₂), 6.96 (3H, s, ArHortho and 2xArH meta to OMe), 7.55-8.05 (4H, m, isoquinoline H₄, H₆, H₇,H₈), 8.44 (1 H, d, J5.8 Hz, isoquinoline H₃) and 9.23 (1 H, sisoquinoline H₁) m/z 319 (M⁺, 24%), 252 (32), 251 (M⁺ -cyclopentyl), 236(55), 209 (13), 208 (13), 135 (49), and 77 (10).

l) 2-(3-Cyclopentyloxy-4-methoxyphenyl)pyridine

from Intermediate 3 (423 mg; 1.79 mmol) and 2-bromopyridine (325 mg;2.06 mmol), to yield the title compound (0,475 g) as a white crystallinesolid [m.p. 74°-75° C. (n-hexane)]. δ_(H) (CDCl₃) 1.6-2.1 (8H, br m,(CH₂)₄, 3.87 (3H, S, OMe), 4.91 (1H, br m, OCHCH₂), 6.90 (1 H, d, J8.4Hz, ArH ortho to OMe), 7.0-7.2 (1 H, m, ArH), 7.47 (1 H, dd, J8.4,2.1HZ, ArH para to OCp), 7.55-7.7 (3H, m, ArH) and 8.59 (1H, dm, J4.7Hz, ArH ortho to pyN); m/z 269 (M⁺, 11%), 202 (15), 201 (M⁺ -Cp, 100),186 (56 ), 158 (16), 32 (13), and 28 (53).

Treatment of the title compound with ethereal HCl afforded thehydrochloride salt as a yellow solid [.m.p. 167°-170° C. (dec) (fromether/ethanol)]. Found: C, 66.67; H, 6.62; N, 4.54. C₁₇ H₁₉ NO₂ HClrequires C, 66.77; H, 6.59; N, 4.58%.

m) 2-(3-Cyclopentyloxy-4-methoxyphenyl)benzonitrile

From Intermediate 3 (1.016 g) and 2-Bromobenzonitrile (0,965 g). Columnchromatography [SiO₂ ; dichloromethane] furnished the title compound(1.175 g) as colourless oil. Found: C, 77.00; H, 6.52; N. 4.54. C₁₉ H₁₉NO₂ requires C, 77.52; H, 6.85; N, 4.76%.

EXAMPLE 4

3-(3-Cyclopentyloxy-4-methoxyphenyl)pyridine hydrochloride

A solution of Intermediate 2 (2.812 g, 10.37 mmol) in DME (filteredthroughAl₂ O₃) (25 ml) was treated with tetrakis(triphenylphosphine)palladium[O] (0.36 g, 0.31 mmol) and stirred at RT for 0.25 h.Diethyl(3-pyridyl)borane (1.50 g, 10.20 mmol) and sodium carbonate [(2.2g, 20.7 mmol) in 10 ml H₂ O] was added and the mixture heated to refluxfor 5 h. The mixture was cooled and partitioned between EtOAc (50 ml)and brine (30 ml). The organic layer was separated and combined withafurther EtOAc wash (25 ml). The organic extract was washed (brine; 20ml), dried (Na₂ SO₄), and concentrated in vacuo to yield a yellowoilwhich was subjected to flash column chromatography (SiO₂ :Et₂O-hexane; 1:1) to give a pale yellow oil (2.14 g). The oil was dissolvedin ethanol and treated with Et₂ O-HCl until the title compound justbegan to precipitate. The mixture was stored at 4° C. for 72 h, then theproduct was collected by filtration, washed with Et₂ O and dried invacuo to yield the title compound (1.76 g) as white needles. Found: C,66.61; H, 6.60; N, 4.47. C₁₇ H₁₉ NO₂.HCl requiresC, 66.77; H, 6.59; N,4.58%). m/z 269 (M⁺ -HCl, 26%), 202 (34), 201 (M⁺ -HCl-cyclopentyl,100%), 187 (16), 186 (93), 158 (30).

EXAMPLE 5

4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylquinoline hydrochloridehemihydrate

A solution of 4-chloroquinaldine (2.25 g, 12.7 mmol) in dioxane (20 ml)wastreated with tetrakis(triphenylphosphine)palladium[O] (440 mg, 0.38mmol) and stirred at RT for 0.5 h. Intermediate 3 (3.00 g, 12.71 mmol)and Na₂ CO₃ [(2.7 g, 25.4 mmol) in ml H₂ O] was added and the mixtureheated to reflux for 18 h. The mixture was cooled and diluted withEtOAc(50 ml) and brine (25 ml). The organic phase was separated and combinedwith a further EtOAc extract (50 ml). The extract was washed (brine; 25ml), dried (Na₂ SO₄), and concentrated in vacuo to give a pale brown oilwhich was flash column chromatographed (SiO₂ ; Et₂ O-hexane; 1:1) togive a colourless oil which crystallised to give a white solid onstanding (3.78 g). The solid (0.5 g) was dissolved in ethanoI-HCl thendiluted with Et₂ O to the crystallising point. The mixture was allowedto stand in the refrigerator for 48 h, then the supernatant was removedby decantation. The residue was washed with ether then dried in vacuo toafford the title compound as a yellow solid. δ_(H) (CDCl₃ ; 80 MHz)1.5-2.1 (8H, m (CH₂)₄), 3.19(3H, s, ArMe), 3.94 (3H, s, OMe), 4.79 (1H,br m, OCHCH₂), 7.01 (1H, s, ArH), 7.05 (2H, s, ArH), 7.44 (1H, s,quinoline H₃), 7.6-8.2 (4H, m, quinoline H₅, H₆, H₇, H₈), 8.99 (1 H, d,J8.0 Hz, NH). m/z 333(M⁺ -HCl, 12%), 266 (19), 265 (M⁺ -HCl-cyclopentyl,100%) 250 (19), and 222 (15).

EXAMPLE 6

1-Amino-4-(3-Cyclopentyloxy-4-methoxyphenyl)isoquinoline hydrochloride

To a solution of the compound of Example 2 (1.0 g, 3.13 mmol) in drytoluene (20 ml) under nitrogen at room temperature was added a 50% wtsuspension of sodium amide in toluene (estimated excess) and this heatedto reflux overnight. The reaction mixture was quenched cautiously withwater (40 ml) and allowed to stir under nitrogen for 10 mins beforepouring into brine (40 ml) and extracting with EtOAc (3×40 ml). Theorganic extract was washed with brine (60 ml), dried (MgSO₄) and thesolvent removed in vacuo. The brown oily residue, was subjected to flashchromatography [EtOAc, hexane, 1:3 (500 ml); 1:1 (500 ml) the EtOAc with2ml of concentrated NH₃ (1000 ml)] to yield an off-white solid (598mg)which was dissolved with heating in propan-2-ol and precipitated withdiisopropyl ether to afford a pale brown powder (290 mg). The powder wastreated with ethereal HCl/ethanol to yield the title compound as anoff-white solid. [m.p. 253°-257° C. (dec.)]. Found C, 67.63;H, 6.23; N,7.55. C₂₁ H₂₃ N₂ O₂.HCl requires C, 68.01; H, 6.25; N, 7.55%. m/z 334 (M⁺ -HCl, 46%), 266 (M⁺ -HCl-cyclopentyl, 100).

EXAMPLE 7

2-Cyclopentyloxy-4-(3-nitrophenyl)anisole

i) A mixture of Intermediate 1 (2.50 g) and 3-nitrobenzeneboronic acid(3.10 g) was coupled using the Suzuki conditions exemplified in Example1 to afford 2-cyclopentyloxy-4-(3-nitrophenyl)phenol (1.0 g) as yellowplates.

ii) 2-Cyclopentyloxy-4-(3-nitrophenyl)phenol (600 mg, 2.45 mmol) wasdissolved in DMF (40 ml) and treated with Cs₂ CO₃ (730 mg, 2.24 mmol)and cyclopentyl bromide (0.32 ml, 2.94 mmol). After stirring overnightat RT some of the phenol remained (SiO₂ :t.l.c, CH₂ Cl₂). Cs₂ CO₃ (870mg, 2.67 mmol) and cyclopentyl bromide (0.32 ml, 2.94 mmol) were added.After stirring at RT for 3 h the phenol had been consumed. The reactionmixture was filtered and concentrated in vacuo. The residue wasdissolved in Et₂ O (50 ml), filtered, and concentrated in vacuo to givea yellow solid which was recrystallised fromdichloromethane/hexane toafford the title compound (378 mg) as yellow needles. δ_(H) (CDCl₃ ; 80mHz) 1.5-2.1 (8H, br m, (CH₂)₄), 3.87 (3H, s, OMe), 4.84 (1H, br m,OCHCH₂), 6.91 (1 H, d, J9.1 Hz, ArH ortho to OMe), 7.0-7.2 (2H, m, ArHmeta to OMe), 7.54 (1H, d, J7.5 Hz, ArH meta to NO₂), 7.80 (1 H, ca. dt,Jca 7.5, 1.5 Hz, ArH para to NO₂), 8.09 (1 H, ca. dt, J ca.8, 1.5 Hz,ArH parato aryl), 8.33 (1 H, ca. t, J ca 2 Hz, ArH ortho to NO₂ andaryl); m/z313 (M⁺, 7%), 246 (17), 245 (M⁺ -cyclopentyl, 100), 230 (41),202(8), and 139 (9).

EXAMPLE 8

4-(3-Cyclopentyloxy-4-methoxyphenyl)quinoline

A solution of 4-chloroquinoline (2.08 g; 12.71 mmol) in dioxane (30 ml)wastreated with tetrakis (triphenylphosphine)palladium (0) (440 mg; 0.38mmol)and stirred at room temperature for 0.5 hr. Intermediate 3 (3 g;12.71 mmol) and Na₂ CO₃ (2.7 g; 25.4 mmol) in H₂ O (12 ml) (ca 2M) wereadded and the mixture heated to reflux for 18 hr. The reaction mixturewas diluted with EtOAc (50 ml) and brine (25 ml) and the organic layerseparated. The aqueous layer was re-extracted with EtOAc (50 ml) andthecombined organic layer was washed with brine (20 ml), dried (Na₂ SO₄)and concentrated in vacuo to give a pale brown oil (4.91 g). Thecrudeoil was dissolved in Et₂ O-hexane (1:1), and the resulting precipitatecollected by filtration, washed with hexane and dried in vacuoto affordthe title compound as a white solid. Found C, 78.80; H, 6,56; N, 4.30.C₂₁ H₂₁ NO₂ requires C, 78.97; H, 6.63; N, 4.39%. δ_(H) (CDCl₃) 1.5-2.0(8H, m, (CH₂)₄), 3.91 (3H, s,OMe), 4.76 (1H, br m, OCHCH₂), 6.99 (3H, s,ArH), 7.27 (1H, D, J4.7 Hz, quinoline H₃), 7.4-7.7 (2H, m, quinoline H,H), 7.9-8.2 (2H, m, quinoline H, H) and 8.86 (1 H, d, J4.5 Hz, quinolineH₂).

Dissolution of the title compound (0.5 g) in ethanolic HCl followed bydilution with ether afforded the hydrochloride salt (0.63 g)as a yellowpowder. Found C, 70.79; H, 6.14; N, 3.9. C₂₁ H₂₁ NO₂ HCl requires C,70.88; N, 6.23; N, 3.94%. δ_(H) (CDCl₃) 1.5-2.1 (8H, m, (CH₂)₄), 3.95(3H, s, OMe), 4.81 (1 H, br m, OCHCH₂), 7.09 (3H, br s, ArH), 7.7-8.3(SH, m, quinoline H₃, H₅, H₆, H₇, H₈), 8.88 (1 H, d, J8.5 Hz, quinolineH₂) and 9.01 (1 H, br s, NH)

EXAMPLE 9

4-(3-Cyclopentyloxy-4-methoxyphenyl)-5,6,7,8-tetrahydroisoquinoline

To a solution of the compound of Example 2 (0.5 g; 1.57 mmol) in glacialacetic acid (20 ml) was added platinum (IV) oxide (0.1 g; 0.04 mmol).The reaction mixture was purged with N₂ and stirred for 60 h under ahydrogen atmosphere. The reaction mixture was filtered through celiteand the filter washed through with acetic acid (2×10 ml). The filtrateand washings were poured slowly into saturated sodium carbonate solution(100 ml) and extracted with EtOAc (3×60 ml). The combined organic phasewas washed with saturated hydrogen carbonate (2×100 ml) and brine (100ml), dried (MgSO₄) and the solvent removed in vacuo. Purification bycolumn chromatography yielded the title compound (88 mg) δ_(H) (CDCl₃)1.5-2.1 (12H, br m, OCH(CH₂)₄ +CH₂ (CH₂)₂ CH₂), 2.5-2.9 (4H, br m, CH₂(CH)₂ CH₂), 3.85 (3H, s, OMe), 4.75 (1 H, br m, OCHCH₂), 6.7-6.95 (3H,m, ArH ortho+2 x meta to OMe), 8.17 (1H, s, isoquinoline H₁ or H₃) and8.22 (1 H, s, isoquinoline H₁ or H₃).

Treatment of the title compound with ethereal HCl afforded thehydrochloride salt as a yellow crystalline solid (mp 189°-191° C.).Found C, 69.66; H, 7.36; N. 3.83. C₂₁ H₂₅ NO₂. HCl requires C, 70.08; H,7.28; N, 3.89%-m./z 323 (M⁺, 15), 256 (22), 255 (M⁺ -Cp,100), 240 (M⁺-Cp-Me, 28), 170 (13), 141 (12), 36 (16), 32 (14), 28 (54).

EXAMPLE 10

5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine-N-oxide

A solution of 5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine (1.37 g)and 3-chloroperoxybenzoic acid (50.60%) (1.75 g) in dichloromethane (35ml) was stirred at RT and the reaction followed by t.l.c. After 5 days,the reaction mixture was partitioned three times between dichloromethane(50 ml) and 10% aqueous Na₂ SO₃ solution (50 ml). The combined organicphase was washed with 5% aqueous NaOH solution (3×30 ml), brine (30 ml),dried (MgSO₄) and evaporated to afford a tan solid. Flash chromatography[SiO₂ ; dichloromethane/EtOAc, 1:9 then dichloromethane/EtOAc/methane,1:8:1] followed by recrystallisation from EtOAc furnished the titlecompound (390 g) as a white powder (mp 140°-143° C.). Found=C, 67.03; H,6.31; N, 9.81. C₁₆ H₁₈ N₂ O₃ requires C, 67.12; H, 6.34; N, 9.78%.

EXAMPLE 11

a) 3-(3-Cyclopentyloxy-4-methoxyphenyl)pyridazine

b) 4-(3-Cyclopentyloxy-4-methoxyphenyl)pyridazine

To a stirred solution of Intermediate 2 (3 g) in dry THF (30 ml) at -70°C. under an argon atmosphere was added n-butyllithium (1.6M inhexanes)(7.95 ml) over 15 min. The reaction mixture was stirred at -70° C. for15 mins, neat pyridazine (0.96 ml) was then added and the mixtureallowed to warm slowly (ca. 1 h) to room temperature. The solution wasquenched with 5% aqueous acetic acid solution (5 ml) then partitionedseveral times between EtOAc and water. The combined organic phase waswashed with aqueous NaHCO₃, brine, dried (MgSO₄) then concentrated invacuo to yield a dark oil (2.8 g). Flash chromatography [SiO₂ ; 2%methanol/dichloromethane] gave two fractions containing the two titlecompounds.

Recrystallisation (from EtOAc/hexane (1:3)) of the first fraction,followedby suspension in hot Et₂ O, cooling and filtration furnished3-(3-cyclopentyloxy-4-methoxyphenyl)pyridazine (260 mg) as a pale yellowfluffy crystalline solid (mp 112°-114° C.). Found C, 70.99; H, 6.69; N,10.20. C₁₆ H₁₈ N₂ O₂ requires C, 71.09; H,6.71; N, 10.36%.

Recrystallisation from EtOAc/hexane (1:5), of the second fractionfollowed by flash chromatography [SiO₂ ; 1% methanol/dichloro methane]then recrystallisation from (EtOAc/hexane, 1:4) furnished4-(3-Cyclopentyloxy-4-methoxyphenyl)pyridazine (200 mg) as pale yellowneedles (mp 100°-102° C.). Found C, 71.16; H, 6.70; N, 10.17. C₁₆ H₁₈ N₂O₂ requires C, 71.09; H, 6.71; N, 10.36%.

EXAMPLE 12

5-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulphonyl pyrimidine

To a cold (0° C.) solution of the compound of Example 1e (5.82 g)indichloromethane (100 ml) was added solid 3-chloroperoxybenzoic acid inbatches. The temperature was kept below 10° C. and the stirring carriedon for 1 h. The precipitate was filtered off and washed withdichloromethane (4×50 ml). The combined organic extract was washed with10% aqueous Na₂ SO₃ (2×50 ml), saturated aqueous NaHCO₃ (3×50 ml), brine(50 ml), dried (MgSO₄) and evaporated in vacuo. Flash chromatography[SIOC₂ ; Et₂ O/hexane,1:4] followed by recrystallisation from EtOAcfurnished the title compound (3.7 g) as a white solid (mp 188°-190° C.).Found C, 58.39; H, 5.76; N, 8.06. C₁₇ H₂₀ N₂ O₄ S requires C, 58.60; H,5.79; N, 8.04%.

EXAMPLE 13

a) 2-Amino-5-(3-cyclopentyloxy-4-methoxyohenyl)pyrimidine

b) 5-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methoxy pyrimidine

A solution of the compound of Example 12 (1.0 g) in 2M ammonia andmethanol(2.88 ml) in dichloromethane (5 ml) was stirred for 2 days.Ammonia solution (3 ml) was added and the reaction mixture stirred atroom temperature for a further 6 days. The solvent was removed in vacuoand theresidue purified by flash chromatography [SIO₂ ; 2% methanol,dicholoromethane then 5% methanol/dichloromethane] to give two fractionscontaining the two title compounds.

Concentration in vacuo of the first fraction gave a white crystallinesolidwhich was recrystallised from methanol/hexane to furnish5-(3-cyclopentyloxy-4-methoxyphenyl)-2-methoxy pyrimidine (380 mg) as awhite fluffy solid (mp 91°-93° C.). Found C, 68.05; H, 6.64;H, 9.23. C₁₇H₂₀ N₂ O₃ requires C, 67.98; H, 6.71; N, 9.33%.

Concentration in vacuo of the second fraction gave a white solid.Recrystallisation from EtOAc/hexane (1:1) furnished2-amino-5-(3-cyclopentyloxy-4-methoxyphenyl)pyrimidine as a whitecrystalline powder (50 mg) (mp 167°-169° C.). Found C, 67.25; H, 6.77;N, 14.66. C₁₆ H₁₉ N₃ O₂ requires C, 67.35; H, 6.71; N, 14.73%

EXAMPLE 14

5-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrimidine carbonitrile

To a solution of potassium cyanide (205 mg) in dry DMF (10 ml) was addedthe compound of Example 12 (1.0 g) and the reaction mixture stirred atroom temperature for 3 hr then at 50° C. for 2 h. The reaction mixturewas poured into a saturated NaHCO₃ solution (2.5 g Na₂ CO₃ in 120 mlice). The resulting yellow precipitate was filtered offand washed withwater. Recrystallisation from EtOAc/hexane (1:2) gave the title compound(575 mg) as yellow needles (mp 121°-123° C.).Found C, 69.15; H, 5.73; N,14.13. C₁₇ H₁₇ N₃ O₂ requires C, 69.14; H, 5.80; N, 14.23%.

EXAMPLE 15

5-(3-Cyclopentyloxy-4-methoxyphenyl)pyrimidine-2-carboxamide

To a stirred mixture of the compound of Example 14 (1.3 g) in ethanol (8ml) was added hydrogen peroxide (40 vols, 15 ml) and 6M aqueous NaOH (6ml). After 15 min, the reaction mixture was diluted with water (75 ml)andthe white solid filtered off. Recrystallisation from acetonitrilefurnishedthe title compound (200 g) as small white plates(mp235°-238°C.). Found C, 65.06; H, 6.09; N, 13.44. C₁₇ H₁₉ N₃ O₃requires C, 65.16; H, 6.11; N, 13.41%.

The activity and selectivity of compounds according to the invention wasdemonstrated in the following tests.

1. Isolated Enzyme

The potency and selectivity of the compounds of the invention wasdetermined using a battery of distinct PDE isoenzymes as follows:

i. PDE I, rabbit heart

ii. PDE II, rabbit heart

iii. PDE III, rabbit heart

iv. PDE IV, HL60 cells.

The enzymes were purified to kinetic homogeneity using standardchromatographic techniques.

Phosphodiesterase activity was assayed as follows. The reaction wasconducted in 150 μl of standard mixture containing (finalconcentrations): 50 mM TES-NaOH buffer (pH 7.5), 10 mM MgCl₂, 0.1 μM [³H]-cAMP and vehicle or various concentrations of the test compounds. Thereaction was initiated by addition of enzyme and conducted at 30° C. forbetween 5 to 30 mins. The reaction was terminated by addition of 50 μl2% trifluoroacetic acid containing [¹⁴ C]-5'AMP for determining recoveryof the product. An aliquot of the sample was thenapplied to a column ofneutral alumina and the [³ H]-cAMP eluted with 10 ml 0.1 TES-NaOH buffer(pH8). The [³ H]-5'-AMP product was eluted with 2 ml 2M NaOH into ascintillation vial containing 10 ml of scintillation cocktail. Recoveryof [³ H]-5'AMP was determined using the [.sup. 14 C]-5'AMP and allassays were conducted in the linear range of the reaction.

Compounds according to the invention were able to inhibit the action ofthePDE IV HL60 enzyme at concentrations at which they had little or noeffect on the action of each of the other PDE isoenzymes. Thus,compounds of the Examples have approximate Ki values (Ki PDEIV HL60 at 1μM) in the nM-μM range, for example the compounds of Examples 2, 4 and 7have approximate Ki values of 180 nM, 270 nM and 250 nM respectively.

2. The Elevation of cAMP in Leukocvtes

The effect of compounds of the invention on intracellular cAMP wasinvestigated using human neutrophils or guinea pig eosinophils. Humanneutrophils were separated from peripheral blood, incubated withdihydrocytochalasin B and the test compound for 10 min and thenstimulatedwith FMLP. Guinea pig eosinophils were harvested by peritoneallavage of animals previously treated with intra-peritoneal injections ofhuman serum. Eosinophils were separated from the peritoneal exudate andincubated with isoprenaline and test compound. With both cell types,suspensions were centrifuged at the end of the incubation, the cellpellets were resuspended in buffer and boiled for 10 min prior tomeasurement of cAMP by specific radioimmunoassay (DuPont).

The most potent compounds induced a concentration-dependent elevation ofcAMP in neutrophils and/or eosinophils at concentrations of 1 nM to 1μM.

3. Suppression of Leukocyte Function

Compounds of the invention were investigated for their effects onsuperoxide generation and chemotaxis of human neutrophils. Neutrophilswere separated from peripheral blood, incubated with dihydrocytochalasinBfor superoxide generation only and test compound prior to stimulationwith FMLP. The most potent compounds caused a concentration-dependentinhibition of superoxide generation and chemotaxis at concentrations of0.1 nM to 1 μM.

4. Relaxation of Constricted Airway Smooth Muscle in vitro

The effects of compounds of the invention on guinea-pig isolatedtracheal smooth muscle were investigated. Isolated tracheal rings weresuspended inorgan baths and immersed in oxygenated Krebs' solution. Thesmooth muscle was contracted with submaximal concentrations of histamineor carbachol prior to the addition of increasing concentrations of testcompound to theorgan baths. The most potent compounds caused aconcentration-dependent reversal of both histamine and carbachol-inducedcontractions at concentrations of 1 nM to 100 μM. The compounds weregenerally more potent in reversing histamine-induced tone thancarbachol-induced tone.

5. Effects on Cardiac Muscle in vitro

Compounds of the invention have been tested for their effects onisolated cardiac muscle. Right atrial and papillary muscles weredissected out fromthe hearts of guinea pigs and suspended in organ bathsfor measuring the rate (chronotropic) of spontaneously beating atria andforce (inctropic) of the electrically stimulated papillary muscle. Inthese preparations, selective PDE IV inhibitors such as rolipram do nothave any direct effects whereas selective PDE III inhibitors such asmilrinone have positive chronotropic and inctropic effects. Thenon-specific PDE inhibitor theophylline, which is used in asthma as abronchodilator, also causes significant cardiovascular changes such astachycardia. Selective PDE IV inhibitors have advantage overtheophylline, therefore, through reduced cardiovascular side effects.The most potent and selective compounds of the invention had no directeffects on the atrial and papillary muscles in vitro at concentrationsup to 100 μM but in combination with PDE III inhibitors, theseinhibitors showed an enhancement of chronotropic and inctropic activity,typical of selective type IV inhibitors.

6. Anti-allergic Activity in vivo

Compounds of the invention have been tested for effects on anIgE-mediated allergic pulmonary inflammation induced by inhalation ofantigen by sensitised guinea pigs. Guinea pigs were initially sensitisedto ovalbuminunder mild cyclophosphamide-induced immunosuppression, byintraperitoneal injection of antigen in combinations with aluminiumhydroxide and pertussis vaccine. Booster doses of antigen were given twoand four weeks later and at six weeks, animals were challenged withaerosolised ovalbuminwhilst under cover of an intraperitoneallyadministered anti-histamine agent (mepyramine). After a further 48 h,bronchial alveolar lavages (BAL)were performed and the numbers ofeosinophils and other leukocytes in the BAL fluids were counted. Thelungs were also removed for histological examination for inflammatorydamage. Administration of compounds of the invention (0.1-10 mg/kgi.p.), up to three times during the 48 h followingantigen challenge,lead to a significant reduction in the eosinophilia and the accumulationof other inflammatory leukocytes. There was also less inflammatorydamage in the lungs of animals treated with compounds of the invention.

7. Effects on Pulmonary Dynamics

Compounds of the invention have been tested for their effects onozone-induced hyperreactivity of the airways of guinea pigs. Followingtheinhalation of ozone, guinea pigs become very much more sensitive tothe bronchoconstrictor effects of inhaled histamine than naive animals.There is a pronounced shift to the left (10-30 fold) of the doseresponse curve to histamine and a highly significant increase in themaximum increase in pulmonary resistance. Compounds of the inventionadministered 1 h prior toozone by the intraperitoneal (0.01-1 mg/kg) ororal (0.1-10 mg/kg) route caused a dose-dependent inhibition ofozone-induced hyperreactivity.

In general, in our tests above, compounds of the invention have had noobserved toxic effects when administered to animals at the doses shown.

We claim:
 1. A compound of formula (1) ##STR9## wherein: Y is halogen or--OR¹, where R¹ is substituted or unsubstituted C₁₋₆ alkyl, said R¹substituent being halogen;R² is substituted or unsubstituted C₃₋₈cycloalkyl or substituted or unsubstituted C₃₋₈ cycloalkenyl, said R²substituents being halogen, C₁₋₆ alkyl, hydroxyl or C₁₋₆ alkoxy; R³ issubstituted or unsubstituted pyrimidinyl or substituted or unsubstitutedpyridazinyl, said R³ substituents being C₁₋₆ alkyl; C₁₋₆ alkoxy; C₂₋₆alkylenedioxy; C₅₋₇ cycloalkoxy; haloC₁₋₆ alkyl; C₁₋₆ alkylthio; nitro;carboxyl (--CO₂ H) and carboxyl esterified by C₁₋₆ alkyl, C₆₋₁₂ aryl,C₁₋₃ alkyl or C₆₋₁₂ aryl; C₁₋₆ alkanoyl (--C(═O)Alk¹); sulphonyl (--SO₃H) C₁₋₆ alkylsulphonyl (--SO₂ Alk¹); aminosulphonyl (--SO₂ NH₂); C₁₋₆alkylaminosulphonyl (--SO₂ NHAlk¹); C₁₋₆ dialkylaminosulphonyl (--SO₂N(Alk¹)₂); carboxamido (--CONH₂); C₁₋₆ alkylaminocarbonyl (--CONHAlk¹);C₁₋₆ dialkylaminocarbonyl (--CON(Alk¹)₂); sulphonylamino (--NHSO₂ H);C₁₋₆ alkylsulphonylamino (--NHSO₂ Alk¹); C₁₋₆ dialkylsulphonylamino(--NSO₂ (Alk¹)₂); C₁₋₆ alkanoylamino (--NHC(═O)Alk¹); or C₁₋₆alkanoylaminoC₁₋₆ alkyl (--N(Alk¹)C(═O)Alk¹); where Alk.sup. 1 isstraight or branched C₁₋₆ alkylene; and X is --O--, --S--, or --N(R⁵)--,where R⁵ is hydrogen or C₁₋₆ alkyl;or a salt, solvate, hydrate orN-oxide thereof.
 2. A compound according to claim 1 wherein X is --O--.3. A compound according to claim 1 wherein Y is --OR¹, where R¹ issubstituted or unsubstituted C₁₋₆ alkyl, said R¹ substituent beinghalogen.
 4. A compound according to claim 1 wherein R² is substituted orunsubstituted C₃₋₈ cycloalkyl, said R² substituent being halogen, C₁₋₆alkyl, hydroxyl or C₁₋₆ alkoxy.
 5. A compound according to claim 1wherein R³ is pyrimidinyl or pyridazinyl.
 6. A compound of formula (2)##STR10## wherein: R² is substituted or unsubstituted C₃₋₈ scycloalkyl,said R² substituent being halogen, C₁₋₆ alkyl, hydroxyl or C₁₋₆ alkoxy;andR³ is substituted or unsubstituted pyrimidinyl or substituted orunsubstituted pyridazinyl, said R³ substituents being C₁₋₆ alkyl; C₁₋₆alkoxy; C₂₋₆ alkylenedioxy; C₅₋₇ cycloalkoxy; haloC₁₋₆ alkyl; C₁₋₆alkylthio; nitro; carboxyl (--CO₂ H) and carboxyl esterified by C₁₋₆alkyl, C₆₋₁₂ arylC₁₋₃ alkyl or C₆₋₁₂ aryl; C₁₋₆ alkanoyl (--C(═O)Alk¹);sulphonyl (--SO₃ H); C₁₋₆ alkylsulphonyl (--SO₂ Alk¹); aminosulphonyl(--SO₂ NH₂); C₁₋₆ alkylaminosulphonyl (--SO₂ NHAlk¹); C₁₋₆dialkylaminosulphonyl (--SO₂ N(Alk¹)₂); carboxamido (--CONH₂); C₁₋₆alkylaminocarbonyl (--CONHAlk¹); C₁₋₆ dialkylaminocarbonyl(--CON(Alk¹)₂); sulphonylamino (--NHSO₂ H); C₁₋₆ alkylsulphonylamino(--NHSO₂ Alk¹); C₁₋₆ dialkylsulphonylamino (--NSO₂ (Alk¹)₂); C₁₋₆alkanoylamino (--NHC(═O)Alk¹); or C₁₋₆ alkanoylaminoC₁₋₆ alkyl(--N(Alk¹)C(═O)Alk¹); where Alk¹ is straight or branched C₁₋₆alkylene;or a salt, solvate, hydrate or N-oxide thereof.
 7. A compoundaccording to claim 6 wherein R² is cyclopentyl.
 8. A compound accordingto claim 6 wherein R³ is substituted or unsubstituted 5-pyrimidinyl. 9.A compound of formula (8) ##STR11## wherein: R⁸ is substituted orunsubstituted cyclopentyl, said R⁸ substituent being halogen, C₁₋₆alkyl, hydroxyl or C₁₋₆ alkoxy; andR⁹ is substituted or unsubstituted5-pyrimidinyl, wherein said R⁹ substituents are C₁₋₆ alkyl; C₁₋₆ alkoxy;C₂₋₆ alkylenedioxy; C₅₋₇ cycloalkoxy; haloC₁₋₆ alkyl; C₁₋₆ alkylthio;nitro; carboxyl (--CO₂ H) and carboxyl esterified by C₁₋₆ alkyl, C₆₋₁₂arylC₁₋₃ alkyl or C₆₋₁₂ aryl; C₁₋₆ alkanoyl (--C(═O)Alk¹); sulphonyl(--SO₃ H); C₁₋₆ alkylsulphonyl (--SO₂ Alk¹); aminosulphonyl (--SO₂ NH₂);C₁₋₆ alkylaminosulphonyl (--SO₂ NHAlk¹); C₁₋₆ dialkylaminosulphonyl(--SO₂ N(Alk¹)₂); carboxamido (--CONH₂); C₁₋₆ alkylaminocarbonyl(--CONHAlk¹); C₁₋₆ dialkylaminocarbonyl (--CON(Alk¹)₂); sulphonylamino(--NHSO₂ H); C₁₋₆ alkylsulphonylamino (--NHSO₂ Alk¹); C₁₋₆dialkylsulphonylamino (--NSO₂ (Alk¹)₂); C₁₋₆ alkanoylamino(--NHC(═O)Alk¹); or C₁₋₆ alkanoylaminoC₁₋₆ alkyl (--N(Alk¹)C(═O)Alk¹);where Alk¹ is straight or branched C₁₋₆ alkylene;or a salt, solvate,hydrate or N-oxide thereof.
 10. A compound of claim 9 wherein R⁹ issubstituted or unsubstituted 5-pyrimidinyl.
 11. A compound according toclaim 8 which is selected from the group consistingof:5-(3-cyclopentyloxy-4-methoxyphenyl)pyrimidine; and5-(3-cyclopentyloxy-4-methoxyphenyl)pyrimidine-2-carboxamide.
 12. Apharmaceutical composition comprising a compound of formula (1)##STR12## wherein: Y is halogen or --OR¹, where R¹ is substituted orunsubstituted C₁₋₆ alkyl, said R¹ substituent being halogen;R² issubstituted or unsubstituted C₃₋₈ scycloalkyl or substituted orunsubstituted C₃₋₈ scycloalkenyl, said R² substituents being halogen,C₁₋₆ alkyl, hydroxyl or C₁₋₆ alkoxy; R³ is substituted or unsubstitutedpyrimidinyl or substituted or unsubstituted pyridazinyl, said R³substituents being C₁₋₆ alkyl; C₁₋₆ alkoxy; C₂₋₆ alkylenedioxy; C₅₋₇cycloalkoxy; haloC₁₋₆ alkyl; C₁₋₆ alkylthio; nitro; carboxyl (--CO₂ H)and carboxyl esterified by C₁₋₆ alkyl, C₆₋₁₂ arylC₁₋₃ alkyl or C₆₋₁₂aryl; C₁₋₆ alkanoyl (--C(═O)Alk¹); sulphonyl (--SO₃ H); C₁₋₆alkylsulphonyl (--SO₂ Alk¹); aminosulphonyl (--SO₂ NH₂); C₁₋₆alkylaminosulphonyl (--SO₂ NHAlk¹); C₁₋₆ dialkylaminosulphonyl (--SO₂N(Alk¹)₂); carboxamido (--CONH₂); C₁₋₆ alkylaminocarbonyl (--CONHAlk¹);C₁₋₆ dialkylaminocarbonyl (--CON(Alk¹)₂); sulphonylamino (--NHSO₂ H);C₁₋₆ alkylsulphonylamino (--NHSO₂ Alk¹); C₁₋₆ dialkylsulphonylamino(--NSO₂ (Alk¹)₂); C₁₋₆ alkanoylamino (--NHC(═O)Alk¹); or C₁₋₆alkanoylaminoC₁₋₆ alkyl (--N(Alk¹)C(═O)Alk¹); where Alk¹ is straight orbranched C₁₋₆ alkylene; and X is --O--, --S--, or --N(R⁵)--, where R⁵ ishydrogen or C₁₋₆ alkyl; or a salt, solvate, hydrate or N-oxide thereof;together with one or more pharmaceutically acceptable carriers,excipients or diluents.
 13. A method for preventing or treating aninflammatory disease in a patient comprising administering to saidpatient, in combination with a pharmaceutically acceptable carrier, aselective inhibitor of a phosphodiesterase (PDE) IV isoenzyme in anamount sufficient to elevate intracellular levels of adenosine3',5'-cyclic monophosphate (cAMP), said inhibitor comprising a compoundof the formula: ##STR13## wherein: Y is halogen or --OR¹, wherein R¹ issubstituted or unsubstituted C₁₋₆ alkyl, said R¹ substituent beinghalogen;R² is substituted or unsubstituted C₃₋₈ scycloalkyl orsubstituted or unsubstituted C₃₋₈ scycloalkenyl, said R² substituentsbeing halogen, C₁₋₆ alkyl, hydroxyl or C₁₋₆ alkoxy; R³ is substituted orunsubstituted pyrimidinyl or substituted or unsubstituted pyridazinyl,said R³ substituents being C₁₋₆ alkyl; C₁₋₆ alkoxy; C₂₋₆ alkylenedioxy;C₅₋₇ cycloalkoxy; haloC₁₋₆ alkyl; C₁₋₆ alkylthio; nitro; carboxyl (--CO₂H) and carboxyl esterified by C₁₋₆ alkyl, C₆₋₁₂ arylC₁₋₃ alkyl or C₆₋₁₂aryl; C₁₋₆ alkanoyl (--C(═O)AIk¹); sulphonyl (--SO₃ H); C₁₋₆alkylsulphonyl (--SO₂ Alk¹); aminosulphonyl (--SO₂ NH₂); C₁₋₆alkylaminosulphonyl (--SO₂ NHAlk¹); C₁₋₆ dialkylaminosulphonyl (--SO₂N(Alk¹)₂); carboxamido (--CONH₂); C₁₋₆ alkylaminocarbonyl (--CONHAlk¹);C₁₋₆ dialkylaminocarbonyl (--CON(Alk¹)₂); sulphonylamino (--NHSO₂ H);C₁₋₆ alkylsulphonylamino (--NHSO₂ Alk¹); C₁₋₆ dialkylsulphonylamino(--NSO₂ (Alk¹)₂); C₁₋₆ alkanoylamino (--NHC(═O)Alk¹); or C₁₋₆alkanoylaminoC₁₋₆ alkyl (--N(Alk¹)C(═O)Alk¹); where Alk¹ is straight orbranched C₁₋₆ alkylene; and X is --O--, --S--, or --N(R⁵)--, where R⁵ ishydrogen or C₁₋₆ alkyl;or a salt, solvale, hydrate or N-oxide thereof.14. A method according to claim 11 wherein said inflammatory diseasecomprises asthma.
 15. A method according to claim 11 wherein saidinflammatory disease is selected from the group consisting ofinflammatory airway disease, chronic bronchitis, eosinophilic granuloma,inflammatory arthritis, atopic dermatitis, urticaria, allergic rhinitis,adult respiratory distress syndrome and allergic conjunctivitis.
 16. Acompound according to claim 11 which is5-(3-cyclopentyloxy-4-methoxyphenyl)pyrimidine.
 17. A compound accordingto claim 11 which is5-(3-cyclopentyloxy-4-methoxyphenyl)pyrimidine-2-carboxamide.
 18. Apharmaceutical composition comprising, in combination with one or morepharmaceutically acceptable carriers, excipients or diluents, a compoundaccording to claim
 16. 19. A method for preventing or treating aninflammatory disease in a patient comprising administering to saidpatient, in an amount effective to elevate intracellular levels ofadenosine 3',5'-cyclic monophosphate (cAMP), a compound according toclaim
 16. 20. A pharmaceutical composition comprising, in combinationwith one or more pharmaceutically acceptable carriers, excipients ordiluents, a compound according to claim
 17. 21. A method for preventingor treating an inflammatory disease in a patient comprisingadministering to said patient, in an amount effective to elevateintracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP), acompound according to claim 17.